| 21. |
- Jones, Lesley, et al.
(författare)
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Convergent genetic and expression data implicate immunity in Alzheimer's disease
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 11:6, s. 658-671
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Tidskriftsartikel (refereegranskat)abstract
- Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
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| 22. |
- Larochelle, Jean, et al.
(författare)
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Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec.
- 2012
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Ingår i: Molecular genetics and metabolism. - : Elsevier BV. - 1096-7206 .- 1096-7192. ; 107:1-2, s. 49-54
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Tidskriftsartikel (refereegranskat)abstract
- Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994.
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| 23. |
- O'Malley, Grace, et al.
(författare)
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Physical Activity and Physical Fitness in Pediatric Obesity : What are the First Steps for Clinicians? Expert Conclusion from the 2016 ECOG Workshop
- 2017
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Ingår i: International Journal of Exercise Science. - 1939-795X. ; 10:4, s. 487-496
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- One of the main aims of the European Childhood Obesity Group (ECOG) is to assist healthcare workers in delivering evidence-based assessment and treatment of childhood obesity. Every year the ECOG Congress includes working groups whose objective is to highlight concerns faced by clinicians and practitioners who work in the field of pediatric obesity. This year, a working group was devoted to the assessment of physical activity and physical fitness in this population. The present commentary attempts to summarize the main themes identified by practitioners during these workshops in order to provide the basic and essential first steps required to address physical activity and fitness in children with obesity.
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| 24. |
- Perez-Tenorio, Gizeh, et al.
(författare)
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Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
- 2011
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Ingår i: Breast Cancer Research and Treatment. - : Springer Science Business Media. - 0167-6806 .- 1573-7217. ; 128:3, s. 713-723
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Tidskriftsartikel (refereegranskat)abstract
- The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.
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| 25. |
- Perez-Tenorio, Gizeh, 1971-, et al.
(författare)
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Clinical Value of RPS6KB1 and RPS6KB2 Gene Amplification in Postmenopausal Breast Cancer
- 2008
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Tidskriftsartikel (refereegranskat)abstract
- The mammalian target of rapamycin (mTOR) and its substrates the ribosomal S6 kinases (S6K)1 and 2 integrate nutrient and hormonal/growth factor mediated signals and are implicated indiabetes, obesity and cancer. The genes encoding S6K1 (RPS6KB1) and S6K2 (RPS6KB2) aresituated close to well known amplicons but information regarding its expression and clinicalvalue is scarce. In this study we quantified RPS6KB1/2 gene copy number, establishedassociations with other clinical factors and explored their clinical value in breast cancer. RPS6KB1/2 copy number was determined by fast real-time PCR in 207 breast tumors.RPS6KB1 was amplified (≥ 4 copies) in 10.7% (22/206) and RPS6KB2 in 4.3% (9/207) of thetumors. Amplification of RPS6KB1 was associated with HER2 gene amplification (P=0.025)and protein expression (P=0.014) while RPS6KB2 correlated with ER+ status (P=0.046) and CCND1 amplification (P<0.00001). In a multivariate analysis, both genes were independentprognostic factors indicating higher risk to develop recurrences. In terms of loco regionalcontrol, amplification of the RPS6KB1 gene predicted less response to radiotherapy (P=0.035) while RPS6KB2 gene copy gain (≥ 3 copies) indicated increased benefit from tamoxifen (P=0.03) among ER+ patients. S6K1/2 gene amplification could be used as an indicator oftherapy response among postmenopausal breast cancer patients.
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| 26. |
- Pérez-Tenorio, Gizeh, 1971-, et al.
(författare)
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PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer
- 2007
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:12, s. 3577-3584
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The phosphatidylinositol 3'-kinase/Akt pathway is frequently altered in breast cancer. PTEN, a phosphatase that opposes the effect of phosphatidylinositol 3'-kinase, can be mutated or lost, whereas the PIK3CA gene is mutated. These have been proposed as alternative mechanisms, and their clinicalpathology significance is under discussion. In this study, we aimed to explore whether PIK3CA mutations and PTEN loss are mutually exclusive mechanisms, correlate with other known clinicopathologic markers, or have clinical implication in breast cancer. Experimental Design: Exons 9 and 20 of the PIK3CA gene were analyzed in 270 breast tumors, and mutations were detected by single-stranded conformational analysis followed by sequencing. The expression of PTEN was evaluated by immunohistochemistry in 201 tumors. Results: PIK3CA mutations were found in 24% of the tumors and associated with estrogen receptor(+) status, small size, negative HER2 status, high Akt1, and high cyclin D1 protein expression. PTEN was negative in 37% of the cases and PTEN loss was associated with PIK3CA mutations (P = 0.0024). Tumors presenting PTEN loss or both alterations were often estrogen receptor(+), small in size, and HER2(-). PIK3CA mutations predicted for longer local recurrence-free survival. Moreover, PTEN loss by itself or combined with mutated PIK3CA tended to confer radiosensitivity. In addition, the patients with high S-phase fraction had longer recurrence-free survival if they carried mutations in the PIK3CA gene and/or had lost PTEN, whereas the same alterations were associated with shorter recurrence-free survival among patients with low S-phase fraction. Conclusions: PIK3CA mutations and PTEN loss were not mutually exclusive events and associated with similar prognostic factors.
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| 27. |
- Stenmark Askmalm, Marie, et al.
(författare)
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Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients
- 2004
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 43:3, s. 235-244
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Tidskriftsartikel (refereegranskat)abstract
- p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. Postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. No endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083-0.62), whereas no benefit from radiotherapy was found for patients snowing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.
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| 28. |
- Söderlund, Karin, 1979-, et al.
(författare)
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The BRCA1/BRCA2/Rad51 complex is a prognostic and predictive factor in early breast cancer
- 2007
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Ingår i: Radiotherapy and Oncology. - : Elsevier BV. - 0167-8140 .- 1879-0887. ; 84:3, s. 242-251
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: The breast cancer susceptibility genes BRCA1 and BRCA2 interact with Rad51, one of the central components in the homologous recombination repair pathway. This study evaluates the prognostic and predictive role of BRCA1, BRCA2 and Rad51, individually and as a complex, in breast cancer.Material and Methods: Expression of BRCA1, BRCA2 and Rad51 was investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive postoperative radiotherapy or adjuvant chemotherapy (CMF).Results: 53% (112/212) of the tumours had reduced expression of the BRCA1/BRCA2/Rad51 complex. Low expression correlated to high histologic grade (p=0.05). Patients with low expression of the complex developed significantly more local recurrences as compared to patients with high expression (RR=3.20, 95% C.I. 1.48-6.88, p=0.003). Expression of the BRCA1/BRCA2/Rad51 complex was an independent prognostic factor in multivariate analysis (p=0.03). Patients with low expression of the complex responded well to radiotherapy (RR=0.31, 95% C.I. 0.14-0.70, p=0.005), whereas patients with high expression had few local recurrences and no additional benefit from radiotherapy (RR=1.08, 95% C.I. 0.40-2.90, p=0.88).Conclusions: Low expression of the BRCA1/BRCA2/Rad51 complex is a marker of poor prognosis, but predicts good effect of radiotherapy in patients with early breast cancer.
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| 29. |
- Söderlund Leifler, Karin, 1979-, et al.
(författare)
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Intact Mre11/Rad50/Nbs1 complex predicts good response to radiotherapy in early breast cancer
- 2007
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Ingår i: International Journal of Radiation Oncology, Biology, Physics. - : Elsevier BV. - 0360-3016 .- 1879-355X. ; 68:1, s. 50-58
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Post-operative radiotherapy is offered to a majority of breast cancer patients, since it significantly reduces the risk of local recurrence. However, some patients still develop recurrences. Owing to their vital roles in the repair of radiation-induced double-strand breaks, the Mre11/Rad50/Nbs1 (MRN) complex and the ATM protein might be implicated in tumour cell resistance to radiotherapy. The aim of this study was to investigate the expression and predictive role of these DNA repair proteins for the outcome of radiotherapy in breast cancer patients.Patients and Methods: The protein expression of ATM and the proteins in the MRN complex were investigated using immunohistochemistry in tumours from 224 women with early breast cancer, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (CMF).Results: Compared to normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1 and ATM was reduced in a majority of the tumours. Weak expression of the MRN complex was correlated to high histological grade and ER negativity (p=0.01 and p=0.0001). Radiotherapy significantly reduced the risk of local recurrence as compared to chemotherapy (p=0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (RR=0.27, 95% C.I. 0.098-0.72, p=0.009), whereas patients with negative/weak MRN had no benefit of radiotherapy compared to CMF. These results suggest that an intact MRN complex is important for the tumour cell eradicating effect of radiotherapy.
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| 30. |
- Tancin Lambert, Anna, et al.
(författare)
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Biomarkers Predictive of Atrial Fibrillation in Patients with Cryptogenic Stroke. Insights from The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study
- 2023
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 30:5, s. 1352-1363
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are currently no biomarkers used to select cryptogenic stroke (CS) patients for monitoring with insertable cardiac monitors (ICMs), the most effective tool for diagnosing atrial fibrillation (AF) in CS. The purpose of this study was to assess clinically available biomarkers as predictors of AF.METHODS: Eligible CS and cryptogenic transient ischemic attack (TIA) patients underwent 12-month monitoring with ICMs, clinical follow-up, and biomarker sampling. Levels of cardiac and thromboembolic biomarkers, taken within 14 days from symptom onset, were compared between patients diagnosed with AF (n=74) during monitoring and those without AF (n=185). Receiver operating characteristic (ROC) curves were created. Biomarkers reaching area under ROC curve (AUC) ≥ 0.7 were dichotomized by finding optimal cut-off values and used in logistic regression establishing their predictive value for increased risk of AF in unadjusted and adjusted models.RESULTS: B-type natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatine kinase, D-dimer, high-sensitivity cardiac Troponin I and T were significantly higher in the AF than non-AF group. BNP and NT-proBNP reached predefined AUC level, 0.755 and 0.725 respectively. Optimal cut-off values were 33.5 ng/L for BNP, and 87 ng/L for NT-proBNP. Regression analysis showed that NT-proBNP was a predictor of AF in both unadjusted, odds ratio (OR) 7.72 (95% confidence interval [CI] 3.16-18.87), and age and sex adjusted models, OR 4.82 (95% CI 1.79-12.96).CONCLUSION: Several clinically established biomarkers were associated with AF. NT-proBNP performed best as AF predictor and could be used for selecting patients for long-term monitoring with ICMs.
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